Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2′,2′-difluorodeoxycytidine) into its inactive form, 2′,2′-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDDL), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumor Gammaproteobacteria, dependent on bacterial CDDL expression, and abrogated by cotreatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intratumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria.
Bibliographical noteFunding Information:
R.S. is funded by the Israel Science Foundation (grant no. 1877/14), the Moross Integrated Cancer Center, the Fabrikant-Morse Families Research Fund for Humanity, the Hymen T. Milgrom Trust, Rising Tide Foundation, the Dr. Dvora and Haim Teitelbaum Endowment Fund, the Tobias and Toni Gottesfeld Scholarship, and by A. Shashua, Israel. R.S. is the incumbent of the Roel C. Buck Career Development Chair. T.R.G. is funded by the Howard Hughes Medical Institute and by the U.S. National Cancer Institute (grant no. U54CA112962). C.H. is on the scientific advisory board of Evelo Biosciences. J.A.W. is a paid advisor for GlaxoSmithKline, Roche/ Genentech, Novartis, and Bristol-Myers Squibb.
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